Lipid-lowering antidiabetic agent

ABSTRACT

A composition which includes a salt of metformin and the use of the composition for treatment of or use in prediabetes, diabetes, lowering triglycerides and/or other conditions in mammals.

CROSS REFERENCE TO RELATED APPLICATION

The present application claims priority from U.S. provisional patentapplication 61/461,113 filed on Jan. 12, 2011, the contents of which areherein incorporated by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to salts of poly unsaturated fatty acidswith biguanides.

2. Technical Background

Diabetes mellitus has become pandemic and according to a forecast by theWorld Health Organization, there will be a sharp increase in the numberof diabetic patients by the year 2030. This is an ominous forecast,because managing the long-term complications of diabetes, which includenephropathy, neuropathy, retinopathy, and cardiovascular complications,will have a serious impact on public health budgets. The hallmark ofdiabetes is chronically elevated blood glucose levels. It is also knownthat abnormally elevated glucose levels have an adverse impact onglutathione levels in key diabetic tissues. Furthermore, increasedoxidative stress and increased production of reactive oxygen species areimplicated under hyperglycemic conditions.

In spite of the early discovery of insulin and its subsequent widespreaduse in the treatment of diabetes, and the later discovery of and use ofsulfonylureas, and thiazolidenediones, such as troglitazone,rosiglitazone or pioglitazone, as oral hypoglycemic agents, thetreatment of diabetes remains less than satisfactory.

The use of insulin requires multiple daily doses, usually byself-injection. Determination of the proper dosage of insulin requiresfrequent estimations of the sugar in urine or blood. Treatment ofnon-insulin dependent diabetes mellitus (type 2 diabetes, NIDDM) usuallyconsists of a combination of diet, exercise, oral hypoglycemic agents,e.g., thiazolidenediones, and, in more severe cases, insulin. However,the clinically available hypoglycemic agents can either have sideeffects limiting their use, or an agent may not be effective with aparticular patient. In the case of insulin dependent diabetes mellitus(Type I), insulin administration usually constitutes the primary courseof therapy.

The biguanide metformin is a known compound approved by the U.S. Food &Drug Administration for the therapeutic treatment of diabetes. Thecompound and its preparation and use are disclosed, for example, in U.S.Pat. No. 3,174,901. Metformin is orally effective in the treatment oftype 2 diabetes. Metformin (N,N-dimethylimidodicarbonimidic diamide) isa biguanide, anti-hyperglycemic agent currently marketed in the UnitedStates in the form of its hydrochloride salt 1,1-dimethylbiguanidehydrochloride (Formula 1a).

Metformin hydrochloride can be purchased commercially and can also beprepared, for example, as disclosed in J. Chem. Soc., 1922, 121, 1790.

U.S. Pat. No. 7,973,073 B2 (Mylari) describes use of metformin R-(+)lipoate as being useful for treating diabetes or diabetic complications.

U.S. Patent Publication 2005/0165102 describes complexes of drugs(metformin being mentioned) with transport moieties (fatty acids beingmentioned) to enhance absorption and control delivery of the drugs beingused. Among the fatty acid complexing agents mentioned are caprate,laurate, palmitate and oleate.

U.S. Patent Publication 2005/0182029 describes metformin salts oflipophilic acid salts (fatty acids being mentioned), theirpharmaceutical formulations, and methods of administering the metforminsalts for the treatment of hyperglycemia.

According to United Kingdom Perspective Diabetes Study (UKPDS) (Clarkeet al. Diabetologia, 2005, 48, 868-877), metformin therapy wascost-saving and increased quality-adjusted life expectancy. In theUKPDS, overweight and obese patients randomized to initial therapy withmetformin experienced significant reductions in myocardial infarctionand diabetes-related deaths. Metformin does not promote weight gain andhas beneficial effects on several cardiovascular risk factors.Accordingly, metformin is widely regarded as the drug of choice for mostpatients with Type 2 diabetes.

Prediabetes is a syndrome. Many patients with type 2 diabetes and with aprediabetic condition known as metabolic syndrome suffer from a varietyof lipid disorders including elevated triglycerides. The body usestriglycerides to store fat but high (>200 mg/dl) and very high (>500mg/dl) triglycerides are associated with atherosclerosis which increasesthe patients risk of heart attack and stroke.

Incipient diabetes with impaired glucose tolerance is anotherprediabetic condition. Overall, type 2 diabetes and incipient diabeteswith impaired glucose tolerance, are intimately intertwined withobesity, hyperlipidemia, including hypertriglyceridemia, andcardiovascular complications including arrhythmia, cardiomyopathy,myocardial infarction, stroke and heart failure. Clinically,pre-diabetes means that blood sugar level is higher than normal, butit's not yet increased enough to be classified as type 2 diabetes.Still, without intervention, prediabetes is likely to become type 2diabetes over time

Also diabetic patients have impaired circulation which manifests itselfin the slow healing of wounds in the foot and lower leg and puts thepatient at risk for amputation.

Elevated triglycerides may be lowered by diet and exercise. Niacin andomega-3 fatty acids, commonly known as fish oil, are frequently used inthe management of hypertriglyceridemia. Omega-3 fatty acids areunsaturated carboxylic acids which have a terminal double bond threecarbons from the methyl terminus, the 3 position. Omega-3 fatty acidsare commonly extracted from oily fish like salmon, mackerel andmenhaden. They are also extracted from other marine sources like squidand krill. Omega-3 fatty acids are commercially available. The omega-3fatty acids most commonly extracted from fish are eicosapentaenoic acidand docosahexaenoic acid. These compounds have been shown to havebeneficial effects in treating obesity, arrhythmia, and myocardialinfarction and have the structures:

Resolvins are a special class of polyhydroxylated omega-3 fatty acidswhich possess potent antinflammatory and immunoregulatory actions. Thesebiological actions of resolvins are thought to play a significant rolein cardiovascular and diabetic conditions.

SUMMARY OF THE INVENTION

This present invention provides compositions of the formula I:

Wherein HR is an omega-3 polyunsaturated C₁₆₋₂₄ fatty acid optionallysubstituted with from 1-3 hydroxy groups.

The compositions are typically compounds in the form of salts ofmetformin and an omega-3 polyunsaturated fatty acid (RH) in which thebiguanide moiety is protonated and the acid moiety is at least partiallyin ionic form. In some instances, however, for example depending on thepH of the environment, the composition may be in the form of a mixtureof the biguanide and acid components. The invention also providespharmaceutical compositions comprising compositions of formula I andpharmaceutically acceptable excipients. The invention further providesmethods for treating diabetes (especially type 2 diabetes), obesity,cardiac arrhythmia, myocardial infarction and elevated triglycerides.The compounds and compositions of this invention may provide high bloodlevels of the compositions of structure 1, when administered topatients, preferably by oral administration.

Particularly useful compounds are those wherein HR is a fatty acid of 20or 22 carbon atoms with four or five unsaturated bonds in addition tothe required omega-3 unsaturated bond such as 4,7,10,13,16,19docoshexaenoic acid, 5,8,11,14 eicosopentanoic acid and resolvinsderived from these acids such as the 5,12,18 trihydroxy eicosopentanoicacid known as resolvin E1, the 15,18 dihydroxy eicosopentanoic acid,known as resolvin E2, the 7,8,17 trihydroxy docosahexaenoic acid knownas resolvin DE and its 7,16,17 trihydroxy eipmer known as resolvin D2,the 4,11,17 trihydroxy docosahexaenoic acid known as resolvin D3 and the4,5,17 trihydroxy docosahexaenoic acid known as resolvin D4.

The invention relates to a compound of formula I which is a salt ofmetformin and an omega-3 polyunsaturated fatty acid and is meant toinclude any polymorphs, solvates, and hydrates thereof.

In one preferred embodiment, RH is a resolving. In the most preferredembodiment, RH is eicosapentaenoic acid or docosahexaenoic acid.

Compounds of the present invention can be considered as designerdual-acting drugs and additionally possess a means for improving thebioavailability of their component moieties as a result of their highdegree of water solubility.

In certain embodiments, the invention relates to a mixture of metforminor a pharmaceutically acceptable salt thereof, (e.g., hydrochloride,succinate, fumarate) with an omega-3 polyunsaturated fatty acid (RH), ora pharmaceutically acceptable salt thereof. In one preferred embodiment,RH is a resolvin. In the most preferred embodiment, RH iseicosapentaenoic acid or docosahexaenoic acid.

The present invention provides a pharmaceutical composition of theinvention comprising compound of formula I and apharmaceutically-acceptable carrier, vehicle or diluent.

The pharmaceutical composition may, for example, be in a form suitablefor oral administration as a tablet, capsule, pill, powder, sustainedrelease formulation, solution, suspension, for parenteral injection as asterile solution, suspension or emulsion. Such compositions and methodsfor their preparation may be found, for example, in ‘Remington'sPharmaceutical Sciences’, 19th Edition (Mack Publishing Company, 1995).The pharmaceutical composition may be in unit dosage forms suitable forsingle administration of precise dosages. The pharmaceutical compositionwill include a conventional pharmaceutical carrier or excipient and anactive compound.

Formulations suitable for oral administration include solid formulationssuch as tablets, capsules containing particulates, liquids, or powders,lozenges (including liquid-filled lozenges), chews, multi- andnano-particulates, gels, solid solution, liposome, films, ovules, spraysand liquid formulations.

Tablet dosage forms typically also include a disintegrant (such assodium starch glycolate, sodium carboxymethyl cellulose, calciumcarboxymethyl cellulose, polyvinylpyrrolidone, methyl cellulose,microcrystalline cellulose, lower alkyl-substituted hydroxypropylcellulose, starch, pregelatinised starch and sodium alginate) a binder(such as microcrystalline cellulose, gelatin, a sugar, polyethyleneglycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinisedstarch, hydroxypropyl cellulose and hydroxypropyl methylcellulose) and alubricant (such as magnesium stearate, calcium stearate, zinc stearate,sodium stearyl fumarate, and mixtures of magnesium stearate with sodiumlauryl sulfate). A diluent such as lactose, mannitol, xylitol, dextrose,sucrose, sorbitol, microcrystalline cellulose, starch and dibasiccalcium phosphate dehydrate) may also be present. Compositions of theinvention may also be administered for example as capsules made, forexample, from gelatin or hydroxypropylmethylcellulose.

Liquid formulations include suspensions, solutions, syrups and elixirs.Such formulations may be employed as fillers in soft or hard capsulesand typically comprise a carrier, for example, water, ethanol,polyethylene glycol, propylene glycol, methylcellulose, or a suitableoil, Liquid formulations may also be prepared by the reconstitution of asolid, for example, from a sachet. The compositions of the invention mayalso be used in fast-dissolving, fast-disintegrating dosage forms suchas those described in Expert Opinion in Therapeutic Patents, 11 (6),981-986, by Liang and Chen (2001).

Other formulations will be apparent to those skilled in the art.

The invention further provides methods for treatment or lowering therisk of developing conditions such as diabetes, especially type 2diabetes, prediabetes, obesity, arrhythmia, myocardial infarction andstroke by administering therapeutically effective amounts ofcompositions of formula I. Such compositions may also be used to lowertriglyceride levels in a subject and so have a role in treatment ofdiabetes exacerbated with high triglyceride levels. Suitable dosages maybe determined by conventional means.

The triglyceride lowering efficacy of the compounds of the presentinvention can be determined in animal models according to the proceduredescribed by Sidika et al in Journal of Lipid Research, 1992, 33, 1-7.

The following example describes a diabetic rat model that may be usedfor determination of conditions leading to a method for treatment andprevention of post-ischemic damage of the heart and heart tissue.

Spontaneously diabetic Bio-Bred (BB/W) rats from the colony maintainedat the University of Massachusetts Medical Center, Worcester, were usedin this study. BB/W rats were chosen for the current study because theBB/W rats have been considered a useful model of autoimmune humaninsulin-dependent diabetes DM).Like human IDDM, spontaneous diabetesappears during adolescence, with an abrupt clinical onset characterizedby weight loss, hyperglycemia, hypoinsulinemia, and ketonuria. As in thecase of human diabetics, pathological changes in retina, myocardium,liver, kidney, bone metabolism and peripheral nerves have all been welldocumented in BB rats, as described in Diab. Metab. Rev., 8:9 (1992).The BB/W rats were 3 to 4 months old and weighed about 300 to 350 g. TheBB/W rats received daily insulin, which was discontinued 24 h prior toperforming the isolated heart perfusion studies, leading to ahyperglycemic state. The rats were acutely diabetic, receiving 2.02±0.04units of insulin daily, and had been diabetic for at least 12±3 days.The mean blood glucose levels in these diabetic rats were 386±24 mg/dL.The age-matched non-diabetic controls had mean blood glucose levels of92±12 mg/dL.

Isolated Perfused Heart Model

This example describes an isolated perfused rat heart model used indevelopment of the invention. Studies are performed using an isovolumicisolated rat heart preparation. Acutely diabetic male BB/W rats andnon-diabetic age-matched (3 to 4 months old) control are pretreated withheparin (1000 u; IP), followed by sodium pentobarbital (65 mg/kg; IP).After deep anaesthesia is achieved as determined by the absence of afoot reflex, the hearts are rapidly excised and placed into iced saline.The arrested hearts are retrograde perfused in a non-recirculating modelthrough the aorta within 2 minutes following their excision. Leftventricular developed pressure (LVDP) is determined using a latexballoon in the left ventricle with high pressure tubing connected to apressure transducer. Perfusion pressure is monitored using high pressuretubing off the perfusion line. Hemodynamic measurements are recorded ona 4-channel Gould recorder. The system has two parallel perfusion lineswith separate oxygenators, pumps and bubble traps, but commontemperature control allows rapid change perfusion media. The hearts areperfused using an accurate roller pump. The perfusate consists of 118 mMNaCl, 0.47 mM KCl, 12 mM CaCl₂, 12 mM MgCl2, 25 mM NaHCO₃, and thesubstrate 11 mM glucose. The perfusion apparatus is tightlytemperature-controlled, with heated baths being used for the perfusateand for the water jacketing around the perfusion tubing to maintainheart temperature at 37±0.5° C. under all conditions. The oxygenatedperfusate in the room temperature reservoir is passed through 25 ft. ofthin-walled silicone tubing surrounded by distilled water at 37° C.saturated with 95% oxygen. The perfusate then enters the water-jacketed(37° C.) tubing leading to the heart through a water jacketed bubbletrap. This preparation provides excellent oxygenation that routinely hasbeen stable for 3 to 4 hours.

Model For Zero-/Low Ischemia

This example describes a procedure used for study of zero-flow ischemiain diabetic control, diabetic treated, non-diabetic treated and controlisolated hearts. Diabetic control (DC) diabetic treated (DZ) normal (C)control and normal treated (CZ) hearts are subjected to 20 minutes ofnormoxic perfusion followed by 20 minutes of zero-flow ischemia wherethe perfusate flow is completely shut off, followed by 60 minutes ofreperfusion. Hearts are treated with 10 μM metformin eicosapentaenoate.In the metformin eicosapentaenoate treated diabetic group (DZ), heartsare subjected to 10 minutes of normoxic perfusion with normalKrebs-Henseleit buffer and 10 minutes of normoxic perfusion withKrebs-Henseleit buffer containing 10 μM metformin eicosapentaenoate. Thehearts are then subjected to 20 minutes of zero-flow ischemia followedby 60 minutes of reperfusion. In order to avoid any variability inreperfusion conditions, both DC and DZ hearts are reperfused with normalKrebs-Henseleit buffer.

Model For Low-Flow Ischemia

This example describes a procedure used for study of low-flow ischemiain diabetic controls, diabetic treated, non-diabetic treated andnon-diabetic control isolated hearts. Diabetic control hearts (DC) aresubjected to 20 minutes of normoxic perfusion at a flow rate of 12.5mL/minute followed by 30 minutes of low-flow ischemia where theperfusate flow is slowed down to 1.25 mL/min, that is about 10% ofnormal perfusion, followed by 30 minutes of reperfusion at a normal flowrate (12.5 mL/min). In the metformin eicosapentaenoate treated diabeticor non-diabetic groups (DZ or CZ), hearts are subjected to 10 minutes ofnormoxic perfusion (flow rate 12.5 mL/min) with normal Krebs-Henseleitbuffer and 10 minutes of normoxic perfusion with Krebs-Henseleit buffercontaining 10 μM metformin eicosapentaenoate. The hearts are subjectedto 30 minutes of low-flow ischemia (flow rate 1.25 mL/min) and 30minutes of reperfusion at normal flow rate (12.5 mL/min).

Animal models to determine the effects of compounds of the invention ondiabetes and complications of diabetes have been reviewed by Tirabassiet al., ILAR Journal, 2004, 45, 292-302. Antidiabetic activity may alsobe tested according to protocols described in the following patents:U.S. Pat. Nos. 4,340,605; 4,342,771; 4,367,234; 4,617,312; 4,687,777 and4,703,052. Additional references relevant to this application includethe following: French Patent 2796551 and United States Published PatentApplication No. 20030220301.

The present invention is exemplified by the following non-limitingexamples.

EXAMPLE 1 Preparation of[amino(imino)methyl]amino}(dimethylamino)methaniminium(5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentaenoate) delete

N,N-dimethylimidodicarbonimidic diamide. N,N-dimethylimidodicarbonimidicdiamide hydrochloride (4.01 g, 24.3 mmol) was dissolved in 1N sodiumhydroxide (24.2 mL, 24.2 mmol) and stirred at room temperature for 30minutes. The solution was concentrated in vacuo and to the residue wasadded ethanol (80 mL). The mixture was carefully concentrated toazeotropically remove water. To the resulting solid was added EtOH (60mL) and the suspension was filtered to remove precipitated NaCl. Thefiltrate was concentrated and the resulting solid was placed on highvacuum overnight to yield 3.18 g (102%) of metformin as a white solid.

{[Amino(imino)methyl]amino}(dimethylamino)methaniminium(5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentaenoate

Metformin free base (2.67 g, 20.7 mmol) was dissolved in acetonitrile(100 mL) and the resulting solution was filtered through a medium fritto remove a small amount of NaCl that precipitated. To the filtrate wasadded dropwise at room temperature (over a 5 minute period) a solutionof (5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentaenoic acid (5.40 g, 17.8mmol) in acetonitrile (30 mL). A white solid precipitated immediatelyupon addition of the acid. The reaction flask was covered in foil toprotect it from light. The mixture was stirred for one hour at roomtemperature and was then chilled to 0° C. for 1 hour, and then filteredunder an atmosphere of nitrogen. The resulting solid was washed with 50mL acetonitrile and then quickly transferred to a foil-covered roundbottom flask and placed under high vacuum. The material was left underhigh vacuum overnight to yield 6.5 (84%) of the title compound ofExample 1 as a light tan solid; MP 121-124° C. (with decomposition); ¹HNMR (400 MHz, MeOD) d 5.36 (m, 10 H), 3.03 (s, 6 H), 2.84 (m, 8 H), 2.18(m, 2 H), 2.10 (m, 4 H), 1.66 (m, 2 H), 0.97 (t,J=7.57 Hz, 3 H); MS(ESI-) for C₂₀H₂₄O₂ m/z 301.2 (M-H).

EXAMPLE 2 Preparation of {[amino(imino)methyl]amino }(dimethylamino)methaniminium(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoate

N,N-dimethylimidodicarbonimidic diamide. N,N-dimethylimidodicarbonimidicdiamide hydrochloride (4.06 g, 24.5 mmol) was dissolved in IN sodiumhydroxide (24.5 mL, 24.5 mmol) and stirred at room temperature for 30minutes. The solution was concentrated in vacuum and to the residue wasadded ethanol (80 mL). The mixture was carefully concentrated toazeotropically remove water. To the resulting solid was added (60 mL)and the suspension was filtered to remove precipitated sodium chloride.The filtrate was concentrated and the resulting solid was placed on highvaccum overnight to yield 3.22 g (102%) ofN,N-dimethylimidodicarbonimidic diamide as a white solid.

{[Amino(imino)methyl] amino}(dimethylamino)methaniminium(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoate

N,N-Dimethylimidodicarbonimidic diamide (968 mg, 7.61 mmol) wasdissolved in acetonitrile (36 mL) and the resulting solution wasfiltered through a medium frit to remove a small amount of sodiumchloride that precipitated. To the filtrate was added dropwise at roomtemperature (over a 5 minute period) a solution of(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16, 19-hexaenoic acid (2.00 g,6.09 mmol) in acetonitrile (35 mL). A white solid precipitatedimmediately upon addition of the acid. The reaction flask was covered infoil to protect it from light. After stirring for 1 h at roomtemperature, the mixture was chilled to 0° C. for 1 h, and then filteredunder an atmosphere of nitrogen. The solid was washed with 50 mLice-cold acetonitrile and then quickly transferred to a foil-coveredround bottom flask and placed under high vac. The material was leftunder high vacuum overnight to yield 2.54 g (91%) of 1 as a light tansolid. The material was found to be air and light sensitive, and wastherefore stored in an amber vial under nitrogen: MP 124-127° C. (turnedbrown); ¹H NMR (400 MHz, MeOD) 5.36 (m, 12 H), 3.03 (s, 6 H), 2.85 (m,10 H), 2.37 (m, 2 H), 2.19 (m, 2 H), 2.09 (m, 2 H), 0.97 (t, J=7.57 Hz,3 H); MS (ESI-) for C₂₂H₃₂O₂ m/z 327.3 (M-H).

EXAMPLE 3 Preparation of{[amino(imino)methyl]amino}(dimethylamino)methaniminium(5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentaenoate

N,N-dimethylimidodicarbonimidic diamide.

Metformin hydrochloride (331.25 g, 2 moles) was weighed into a 4000 mLbeaker containing a stir bar. 1N KOH (1980 mL, 1.998 moles) was added,the beaker was covered, and the mixture was stirred for 2 h. The solidswere collected by vacuum filtration, and the filtrate was concentratedto a damp solid. Isopropanol (500 mL) was added and after briefswirling, the mixture was concentrated. The residual white solid wasdried for 16 h in a vacuum oven (yield: 269.08 g).

{[Amino(imino)methyl]amino}(dimethylamino)methaniminium(5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentaenoate

Metformin free base (50.10 g, 0.366 mole) was weighed into a 4000 mLbeaker containing a stir bar. CH₃CN (2000 mL) was added and the mixturewas rapidly stirred until all metformin had dissolved. A fine whitesolid was removed by vacuum filtration. After ˜30 min, the hazy filtratewas vacuum filtered through the same medium, and the clear filtrate wastransferred to a 5000 mL 3-necked round bottom flask, which was fittedwith a complete stir shaft assembly, N₂ inlet and addition funnel andbubbler. The funnel was charged with a solution of eicosapentaenoic acid(100.01 g, 0.324 mole) in acetonitrile (500 mL) which was addeddrop-wise over 70 min. After stirring for 2 h, the flask was fitted witha N₂ balloon, sealed, and placed in the refrigerator over-night. Theoff-white solid was collected by vacuum filtration and washed withacetonitrile (500 mL). The damp solid was transferred to a pyrex dish,which was stored in a vacuum oven for 24 h. The oven was vented withnitrogen gas, and the beige solid was coarsely ground in a mortar withpestle then transferred to an amber jar that had been flushed with N₂ toobtain the compound of Example 3 (yield: 130.49 g).

EXAMPLE 4

The solubility of the compound of Example 1 in water was compared withthat of eicosapentaenoic acid (EPA).

Measurement of the water solubility of the test compounds isaccomplished by using methods well known to those skilled in the art.Specifically, to a weighed amount of the test compound of Example 1distilled water is added in small portions until a clear solution isobtained. The total-volume of the solution is measured. The watersolubility is calculated by dividing the weight of the salt, in mg, bythe volume of the solution, in mL. The water solubility of the compoundof Example 1 when measured using the above technique, was determined tobe 50 mg/ml. Likewise, the water solubility of EPA was found to be <0.2mg/mL. The compound of Example 1 is therefore, at least, 250 times moresoluble in water than EPA itself. This is a clear indication of anunexpectedly high degree of bioavailability of the compositions of theinvention. Highly water soluble medicinal preparations, whenadministered orally, result in efficient absorption of such preparationsfrom the gastrointestinal tract into systemic circulation. Suchpreparations permit rapid absorption into the blood stream resulting ina high concentration of the active agent in the blood. Furthermore,water soluble preparations are especially suitable for parenteraladministration, for example, intravenous administration.

1. A composition of structure I, which is a salt of metformin

with at least one polyunsaturated fatty acid represented by RH or amixture of metformin and at least one acid RH or a pharmaceuticallyacceptable solvate or hydrate thereof.
 2. The composition of claim 1 inwhich the polyunsaturated fatty acid RH is an omega-3 fatty acid.
 3. Acomposition of claim 1 wherein RH is an omega-3 polyunsaturated C₁₆₋₂₄fatty acid optionally substituted with from 1-3 hydroxy groups
 4. Acomposition as claimed in claim 2 wherein RH is a fatty acid of 20 or 22carbon atoms with a total of 4- or 5 unsaturated linkages in the fattyacid chain in addition to the omega-3 unsaturated bond.
 5. A compositionof claim 1, wherein RH is selected from the group consisting ofresolvins D1, D2, D3, D4, E1, and E2.
 6. The composition of claim 1 inwhich the polyunsaturated fatty acid RH is eicosapentaenoic acid.
 7. Thecomposition of claim 1 in which the polyunsaturated fatty acid RH isdocosahexaenoic acid.
 8. A composition according to claim 1, wherein Ris a mixture of polyunsaturated fatty acids.
 9. The mixture of claim 8in which the polyunsaturated fatty acid comprises a mixture ofeicosapentaenoic acid and docosahexaenoic acid.
 10. A pharmaceuticalcomposition comprising a compound according to claim 6 and apharmaceutically acceptable carrier, vehicle or diluent.
 11. Apharmaceutical composition comprising a compound according to claim 7and a pharmaceutically acceptable carrier, vehicle or diluent.
 12. Apharmaceutical composition comprising a mixture according to claim 8 anda pharmaceutically acceptable carrier, vehicle or diluent.
 13. A kitcomprising a) a unit dosage form comprising the compound of claim 6; b)instructions on how to use the kit; and c) at least one container forholding the unit dosage forms.
 14. A kit comprising a) a unit dosageform comprising the compound of claim 7; b) instructions on how to usethe kit; and c) at least one container for holding the unit dosageforms.
 15. A kit comprising a) a unit dosage form comprising the saltsof claim 8 b) instructions on how to use the kit; and c) at least onecontainer for holding the unit dosage forms.
 16. A method for treatingdiabetes in a mammal, comprising administering a therapeuticallyeffective amount of a compound according to claim
 6. 17. A method fortreating diabetes in a mammal, comprising administering to said mammal atherapeutically effective amount of a composition according to claim 7.18. A method for treating diabetes in a mammal, comprising administeringto said mammal a therapeutically effective amount of a compositionaccording to claim
 8. 19. A method for treating diabetes in a mammal,comprising administering to said mammal a therapeutically effectiveamount of a composition according to claim
 9. 20. A method of loweringtriglycerides in a mammal, comprising administering to said mammal atherapeutically effective amount of the composition according to claim6.
 21. A method of lowering triglycerides in a mammal, comprisingadministering to said mammal a therapeutically effective amount of thecomposition according to claim
 7. 22. A method of lowering triglyceridesin a mammal, comprising administering to said mammal a therapeuticallyeffective amount of the composition according to claim
 8. 23. A methodof lowering triglycerides in a mammal, comprising administering to saidmammal a therapeutically effective amount of the composition accordingto claim
 9. 24. A method of treating prediabetes in a mammal, comprisingadministering to said mammal a therapeutically effective amount of thecomposition according to claim
 6. 25. A method of treating prediabetesin a mammal, comprising administering to said mammal a therapeuticallyeffective amount of the composition according to claim
 7. 26. A methodof treating prediabetes in a mammal, comprising administering to saidmammal a therapeutically effective amount of the composition accordingto claim
 8. 27. A method of treating prediabetes in a mammal, comprisingadministering to said mammal a therapeutically effective amount of thecomposition according to claim
 9. 28. A method of treating obesity in amammal, comprising administering to said mammal a therapeuticallyeffective amount of the composition according to claim
 6. 29. A methodof treating obesity in a mammal, comprising administering to said mammala therapeutically effective amount of the composition according to claim7.
 30. A method of treating obesity in a mammal, comprisingadministering to said mammal a therapeutically effective amount of thecomposition according to claim
 8. 31. A method of treating obesity in amammal, comprising administering to said mammal a therapeuticallyeffective amount of the composition according to claim
 9. 32. A methodof treating cardiac arrhythmia in a mammal, comprising administering tosaid mammal a therapeutically effective amount of the compositionaccording to claim
 6. 33. A method of treating cardiac arrhythmia in amammal, comprising administering to said mammal a therapeuticallyeffective amount of the composition according to claim
 7. 34. A methodof treating cardiac arrhythmia in a mammal, comprising administering tosaid mammal a therapeutically effective amount of the compositionaccording to claim
 8. 35. A method of treating cardiac arrhythmia in amammal, comprising administering to said mammal a therapeuticallyeffective amount of the composition according to claim
 9. 36. A methodof treating cardiomyopathy in a mammal, comprising administering to saidmammal a therapeutically effective amount of the composition accordingto claim
 6. 37. A method of treating cardiomyopathy in a mammal,comprising administering to said mammal a therapeutically effectiveamount of the composition according to claim
 7. 38. A method of treatingcardiomyopathy in a mammal, comprising administering to said mammal atherapeutically effective amount of the composition according to claim8.
 39. A method of treating cardiomyopathy in a mammal, comprisingadministering to said mammal a therapeutically effective amount of thecomposition according to claim
 9. 40. A method of treating myocardialinfarction in a mammal, comprising administering to said mammal atherapeutically effective amount of the composition according to claim6.
 41. A method of treating myocardial infarction in a mammal,comprising administering to said mammal a therapeutically effectiveamount of the composition according to claim
 7. 42. A method of treatingmyocardial infarction in a mammal, comprising administering to saidmammal a therapeutically effective amount of the composition accordingto claim
 8. 43. A method of treating myocardial infarction in a mammal,comprising administering to said mammal a therapeutically effectiveamount of the composition according to claim
 9. 44. A method for themanufacture of the composition of claim 1 comprising: a) freshlypreparing the free base of metformin from a suitable metformin salt; andb) reacting the freshly prepared free base of metformin witheicosapentaenoic acid, docosahexaenoic acid or a mixture thereof at atemperature between about 1 degree C. and about 60 degree C.